This is a program of multidisciplinary studies of factors influencing the development of and loss of tolerance and dependence to opiates, depressants, cannabinoids, and other recreational drugs used by humans. Clinical evaluation of the effects of various detoxification schemes, antagonists, maintenance drugs, and behavioral modification approaches will be used to assess the effectivenss of psychosocial and chemical interventions in changing drug seeking behavior. Studies of improved methods for managing interpersonal and organizational aspects of outpatient detoxification and methadone maintenance seek to understand characteristics to best utilize different treatment approaches. Laboratory studies include neurophysiologic studies with sleep and waking EEG and evoked potentials, pharmacokinetics, and drug interactions. Biochemical, physiologic, neuroendocrinologic, behavioral and psychometric techniques will be used in the assessment of drug dependent patients, non-patient volunteers and in animal studies. The relationship of endogenous morphine-like factors and naloxone-like factors to morphine action will be evaluated in animal studies and ultimately in humans. Morphine actions and bioamine metabolism will be investigated in subjects on agonist and antagonist maintenance as will the effects of co-existing disease states, hepatocellular disease, respiratory disease on drug effects and disposition. Sleep EEG and pharmacokinetic studies of CNS depressants in aged subjects will investigate the effects of age on drug disposition. An understanding of individual differences in response is of major interest. The development of research strategies appropriate to the study of multiple drugs rather than a narrow specialization in a particular substance or class of drugs is a guiding philosophy.